Enamines, preparation from ketones

Alkylation of enamines prepared from aldehydes was studied by Elkik,210 Opitz and Mildenberg,211 and Williamson 212 and alkylation of enamines prepared from ketones by Stork et al.75 These investigators demonstrated that the ease of alkylation depends on the basicity of the enamine in question. Enamines prepared from the more basic pyrrolidine are alkylated more readily than those obtained from morpholine. Better yields of the enamines (44) from pyrrolidine are obtained, in contrast to the preparations (45) from piperidine (which are bases about as strong as pyrrolidine) this may result from the stabilizing influence of the exocyclic double bond in the polarized form of the pyrrolidine derivative. 

Stork has used the addition of a,/ -unsaturated aldehydes, ketones, esters, and nitriles to enamines prepared from ketones and pyrrolidine, piperidine, or morpholine for the synthesis of a-substituted carbonyl compounds264 266 (Scheme 9). 

No allylation of simple ketones, aldehydes, and esters without additional EWGs occurs. Allylation of ketones is carried out indirectly. For example, enamines, prepared from ketones, are allylated easily and allyl ketones are obtained after hydrolysis (Scheme... 

The imines are prepared by 16-12. The enamine salt method has also been used to give good yields of mono a alkylation of a,P-unsaturated ketones. Enamines prepared from aldehydes and butylisobutylamine can be alkylated by simple primary alkyl halides in good yields. N-alkylation in this case is presumably prevented by steric hindrance. 

Early investigations have demonstrated that aldehydes and ketones can be enantioselectiveiy a-alkyl-ated via Michael reactions of the corresponding enamines, prepared from proline-derived secondary amines.149-156 However, optical purities of the products were generally low and never exceeded 59% ee.iS1 This kind of asymmetric a-alkylation could later be improved, allowing for example the preparation of compound (141) with high ee (Scheme 51).156-160... 

The general procedures for the preparation of enamines, such as condensation of an open-chain aldehyde with a secondary amine in the presence of potassium carbonate or azeotropic removal of water from a solution of a ketone and secondary amine in benzene (frequently in the presence of an acid catalyst), fail to incorporate the desirable feature of stereospecificity. The spectra of a series of enamines prepared from both aldehydes and ketones indicated that the Zs-isomer predominated, but not to the total exclusion of the Z-isomer. 

Enamines represent a final class of vinyl-heteroatom derivatives that can be prepared from ketones and subsequently reduced to alkenes (Scheme 47). Since enamine formation is covered in depth elsewhere, this section will deal only with the reduction of enamines to alkenes. 

They may eliminate so readily that the intermediate imidazoline cannot be isolated, but if the enamine is disubstituted, the 5,5-disubstituted imidazolines which are formed are so stable that it is necessary to heat them with 50% aqueous sulfuric acid, or in anhydrous medium with an equimolar amount of either triethylammonium or pyridinium chlorides, to effect arom-atization. Enamines derived from ketones or hindered aldehydes do not lead to imidazoles, and there are other difficulties (some enamines are difficult to prepare, only aryleneamines give good yields). Nevertheless, the reported results demonstrate the potential of the method [22-24]. 

Enamines are an important class of uncharged synthetic intermediates that exhibit carbanion-like reactivity. They are typically prepared from ketones with one or more a-hydrogens and a secondary amine under acid catalysis ... 

A recent paper describes syntheses of 2ff-thiopyran 1,1-dioxides, for example (25), starting with enamines (24). This reaction sequence has also been applied to enamines prepared from cyclic ketones. 

Enamines are also prepared from azirines by thermolysis/ and from iminium salts by dehydrobromination/" Enaminones are prepared from ketones by reaction with hexamethydisilazane " and from vinamidinium salts by reaction with enolates/ and thioenaminones are now conveniently prepared directly from enaminones/" ... 

The most versatile method for preparing enamines involves the condensation of aldehydes and ketones with secondary amines [Eq. (1)]. Mannich and Davidsen (/) discovered that the reaction of secondary amines with aldehydes in the presence of potassium carbonate and at temperatures near 0° gave enamines, while calcium oxide and elevated temperatures were required to cause a reaction between ketones and secondary amines, although usually in poor yield. The introduction by Herr and Heyl 2-4) of the removal of the water produced in the condensation by azeotropic distillation with benzene made possible the facile preparation of enamines from ketones and disubstituted aldehydes. 

The reaction of the enamines of cyclic ketones with alkyl isocyanates, acyl isocyanates, phenyl isothiocyanates, and acyl isothiocyanates has also been reported 112). The products are the corresponding carboxamides. The products from the isothiocyanates have been utilized as intermediates in the preparation of various heterocyclic compounds 113). 

This is the most common method for the preparation of enamines and usually takes place when an aldehyde or ketone containing an a hydrogen is treated with a secondary amine. The water is usually removed azeotropically or with a drying agent, but molecular sieves can also be used. Stable primary enamines have also been prepared.Enamino-ketones have been prepared from diketones and secondary amines using microwave irradiation on silica gel. ° Secondary amine perchlorates react with aldehydes and ketones to give iminium salts (2, p. 1178). Tertiary amines can only give salts (12). 

For the preparation of enamines or imines from ketones, see Section 356 (Amine-Alkene). 0 1. CFsSOsSiMes, MeCN S... 

Generally, the imine substrates are prepared from the corresponding ketone and amine and are hydrogenated as isolated (and purified) compounds. However, reductive animation where the C = N function is prepared in situ is attractive from an industrial point of view, and indeed there are some successful examples reported below [18, 19]. It is reasonably certain that most catalysts described in this chapter catalyze the addition of H2 directly to the C=N bond and not to the tautomeric enamine C = C bond, even though enamines can also be hydrogenated enantioselectively. 

Michael reaction of enamines of u-alkyl- -keto esters. The chiral lithioen-amine (1), prepared from (S)-valine /-butyl ester, does not react with methyl vinyl ketone or ethyl acrylate unless these Michael acceptors are activated by ClSi(CH3)3... 

The preparation of dithianes from enamines by reaction with trimethylene dithiotosylate (propane-1,3-dithiol di-p-toluenesulfonate) has been applied with enamines derived from oholostan 3 one, aceto-acetic ester, and phenylacetone.6 7 Reactions of trimethylene dithiotosylate with hydroxymethylene derivatives of ketones also give rise to dithianes thus the hydroxymethylene derivative of cholest-4-en-3-one can be converted to 2,2-(trimethylenedithio)cholest-4-en-3-one. 1,3-Dithiolanes are obtained in a similar manner by reaction of ethylene dithiotosylate1 with the appropriately activated substrate.5,7... 

The product in entry 1 of Scheme 2.10 is commonly known as the Wieland-Miescher ketone and is a useful starting material for the preparation of steroids and terpenes. The Robinson annulation to prepare this ketone can be carried out enantioselectively by using the amino acid L-proline to form an enamine intermediate. The 5-enantiomer of the product is obtained in high enantiomeric excess.89 This compound and the corresponding product obtained from cyclopentane-1,3-dione90 are key intermediates in the enantiose-lective synthesis of steroids.91... 

Macrocyclic 2-pyrones (113) and (114) are prepared from enamine (115) and ketene (75HCA2409). Reduction of cyano ketone (116) with LAH affords an amino ketone which spontaneously cyclizes to generate a tetrahydropyridine (117) dehydrogenation by palladium on charcoal produces the aromatized phane (118) (71TL671). 

Both tetrahydro-l,4-oxazine (morpholine) and its thia analogue (thiomorpholine) find application as solvents and bases, morpholine having particular value in synthesis as it is often used to prepare enamines from ketones with a free a-hydrogen atom. TV-Acylation and -alkylation are readily accomplished and a great diversity of TV-substituted morpholines and thiomorpholines are encountered in the patent literature, some having biological activity. 

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